Distinct VEGF functions during bone development and homeostasis.

Vascular endothelial growth factor-A (VEGF) is a key regulator of physiological hemangiogenesis during development, postnatal growth, and homeostasis. It is well known that VEGF is required for effective coupling of angiogenesis to endochondral and membranous bone formation during skeletal development. However, less well known are the roles of VEGF in regulating the differentiation and/or functions of skeletal cells such as chondrocytes, osteoblasts, and osteoclasts. In this review, we discuss some of these functions. During early skeletal development, VEGF is important for the survival of chondrocytes in the hypoxic regions of the cartilage models of future bones, the vascularization of developing bones and proliferation and differentiation of osteoblastic cells. Postnatally, osteoblast-derived VEGF is critical for maintaining bone homeostasis by stimulating the differentiation of mesenchymal stem cells to osteoblasts and repressing their differentiation to adipocytes. Recent data indicate that these effects of VEGF on osteogenic/adipogenic stem cell fates are based on an intracellular (intracrine) mechanism. In contrast, osteoblast-derived VEGF is also known to stimulate the differentiation of monocytes to osteoclasts by a paracrine mechanism. Mice with VEGF-deficient osteoblastic lineage cells exhibit age-dependent loss of bone mass and an increase in bone marrow fat. These changes are similar to the changes associated with osteoporosis in humans. Thus, a better understanding of the intracellular mechanisms by which VEGF regulates osteoblastic and adipogenic differentiation may lead to the identification of new targets for therapies to prevent osteoporotic bone loss.